Glaucoma is one of the leading causes of blindness worldwide. However, a fundamental understanding is still lacking regarding the pathophysiologic mechanisms underlying the optic nerve damage that occurs at the level of the lamina cribrosa. Elevated intraocular pressure (IOP) is known to be the primary cause of glaucoma, but there has been a great deal of debate over the role of IOP fluctuation in the development and progression of the glaucomatous optic neuropathy.
There is ample evidence demonstrating circadian IOP fluctuations, with the peak pressure occurring in the morning upon awakening (Wilensky, 1991; Liu et al., 1999; and Liu et al., 2003). Recently, a variety of studies, including the Advanced Glaucoma Intervention Study (AGIS) have identified IOP fluctuation as an independent risk factor for progression of glaucoma (Asrani et al., 2000; Lee el al, 2007; Hong el al., 2007; and Caprioli and Coleman, 2008). Identifying the neurophysiologic basis of IOP fluctuation and its role in glaucoma progression could profoundly impact the way patients with glaucoma are treated.
IOP varies in a cyclical manner over a 24-hour period in humans (Wilensky, 1991; Liu et al., 1999; Liu et al., 2003), and this circadian variation is conserved in rodents (Valderrama et al., 2005). Applicants hypothesized that the suprachiasmatic nucleus (SCN), which receives direct projections from retinal ganglion cells, may serve as a central control mechanism for these fluctuations. Known as the body's “master time-clock”, the SCN has a variety of functions in regulating circadian activities, including corticosteroid release (Moore and Eichler, 1972; and Cascio et al., 1987) and sleep (Mouret et al., 1978). The SCN also appears to play a role in IOP fluctuations as well. Liu and Shieh have shown that SCN lesions alter circadian fluctuations in IOP (Liu and Shieh, 1995), yet the downstream circuitry mediating this effect is unknown.
As disclosed herein orexin containing neurons located in the dorsornedial hypothalamus (DMH) and/or the perifornical hypothalamus (PeF) are believed to play a role in mediating these circadian fluctuations in IOP. Orexins (also called hypocretins) are neuropeptides first discovered in the late 1990's. There are two forms of orexins, orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively), that are exclusively produced in hypothalamic neurons in the perifornical region (PeF) and lateral hypothalamic area (LHA 1). Orexin A and orexin B were initially identified as endogenous ligands for two orphan G-protein-coupled receptors, now known as orexin receptor-1 (ORX 1) and orexin receptor-2 (ORX2). The amino acid identity between the full length human ORX 1 and ORX2 sequences is 64%. ORX 1 has greater affinity for orexin A than orexin B by 1 order of magnitude. In contrast, ORX2 has similar affinity for both orexin A and orexin B.
Orexins constitute a novel peptide family with no significant structural similarities to known families of regulatory peptides. Orexin A is a 33-amino acid peptide of 3562 Da with two sets of intrachain disulfide bonds. It has an N-terminal pyroglutamyl residue and C-terminal amidation. The primary structure of orexin A predicted from the eDNA sequences is completely conserved among several mammalian species (human, rat, mouse, cow, sheep, dog, and pig). On the other hand, rat orexin B is a 28-amino acid, C-terminally amidated linear peptide of 2937 Da that is 46% ( 13/28) identical in sequence to orexin A. The C-terminal half of orexin B is very similar to that of orexin A (73%; 11115), whereas the N-terminal half is variable. Orexin A and B are produced from a common precursor polypeptide, prepro-orexin.
Classically, the DMH has been recognized as a regulator of the behavioral and physiological responses to emotional stress that includes anxiety-associated behavior (Shekhar, 1993), tachycardia (DeNovellis et al., 1995; Samuels et al., 2002; and Zaretsky et al., 2003), thermogenesis (Zaretskaia et al., 2003; and Madden and Morrison, 2004), and activation of the hypothalamic-pituitary-adrenal axis (Keirn and Shekhar, 1996; Stotz-Potter et al., 1996). Recently, Dr. Anantha Shekhar's laboratory has shown that orexin containing neurons, which are concentrated in the region of the DMH and PeF, play a profound role in mediating the physiologic and behavioral responses to panic (Johnson et al., 2010). Further, Chou and colleagues determined that orexin neurons and other neurons in the DMH receive strong direct and indirect projections from the SCN, and similar to the SCN, lesions in the orexin region affects the circadian pattern of corticosteroid release, sleep, locomotor activity, and feeding (Chou et al., 2003). With a broad array of efferent projections to autonomic sympathetic relays (ter Horst and Luiten, 1986), the DMH and orexin containing neurons are ideally situated to modulate the fluctuations in IOP evoked by circadian activity of SCN neurons.
Consistent with these observations applicants have proposed that the circadian fluctuations in intraocular pressure (IOP) are regulated in part by orexin containing neurons located in the dorsomedial hypothalamus (DMH) and perifornical region (PeF). Furthermore, applicants anticipate that an orexin antagonist could be used to attenuate these fluctuations, making it the first oral medication developed for the chronic treatment of glaucoma.
As disclosed herein, a method is provided for treating glaucoma, comprising the step of administering an orexin inhibitor.